G2Cdb::Human Disease report

Disease id
D00000146
Name
Pseudohypoparathyroidism type 1c
Nervous system disease
no

Genes (1)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00001473 GNAS
GNAS complex locus
Y (11788646) Microinsertion (MI) Y
G00001473 GNAS
GNAS complex locus
Y (11788646) Unknown (?) Y

References

  • GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance.

    Linglart A, Carel JC, Garabédian M, Lé T, Mallet E and Kottler ML

    Department of Pediatric Endocrinology, Groupe Hospitalier Cochin-Saint Vincent de Paul, Assisvance Publique-Hôpitaux de Paris, 75014 Paris, France.

    We conducted clinical and biological studies including screening for mutations in the gene encoding the alpha subunit of G(s) (GNAS1) in 30 subjects (21 unrelated families) with Albright's hereditary osteodystrophy (AHO), pseudohypoparathyroidism (PHP); and decreased erythrocyte G(s) activity (PHP-Ia; n = 19); AHO and decreased erythrocyte G(s) activity (isolated AHO; n = 10); or AHO, hormonal resistance, and normal erythrocyte G(s) activity (PHP-Ic; n = 1). A heterozygous GNAS1 gene lesion was found in 14 of 17 PHP-Ia index cases (82%), including 11 new mutations and a mutational hot-spot involving codons 189-190 (21%). These lesions lead to a truncated protein in all but three cases with missense mutations R280K, V159M, and D156N. In the patient diagnosed with PHP-Ic, G(s)alpha protein was shortened by just four amino acids, a finding consistent with the conservation of G(s) activity in erythrocytes and the loss of receptor contact. No GNAS1 lesions were found in individuals with isolated AHO that were not relatives to PHP-Ia patients (n = 5). Intrafamilial segregation analyses of the mutated GNAS1 allele in nine PHP-Ia patients established that the mutation had either occurred de novo on the maternal allele (n = 4) or had been transmitted by a mother with a mild phenotype (n = 5). This finding is consistent with an imprinting of GNAS1 playing a role in the clinical phenotype of loss of function mutations and with a functional maternal GNAS1 allele having a predominant role in preventing the hormonal resistance of PHP-Ia.

    The Journal of clinical endocrinology and metabolism 2002;87;1;189-97

Literature (1)

Pubmed - human_disease

  • GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance.

    Linglart A, Carel JC, Garabédian M, Lé T, Mallet E and Kottler ML

    Department of Pediatric Endocrinology, Groupe Hospitalier Cochin-Saint Vincent de Paul, Assisvance Publique-Hôpitaux de Paris, 75014 Paris, France.

    We conducted clinical and biological studies including screening for mutations in the gene encoding the alpha subunit of G(s) (GNAS1) in 30 subjects (21 unrelated families) with Albright's hereditary osteodystrophy (AHO), pseudohypoparathyroidism (PHP); and decreased erythrocyte G(s) activity (PHP-Ia; n = 19); AHO and decreased erythrocyte G(s) activity (isolated AHO; n = 10); or AHO, hormonal resistance, and normal erythrocyte G(s) activity (PHP-Ic; n = 1). A heterozygous GNAS1 gene lesion was found in 14 of 17 PHP-Ia index cases (82%), including 11 new mutations and a mutational hot-spot involving codons 189-190 (21%). These lesions lead to a truncated protein in all but three cases with missense mutations R280K, V159M, and D156N. In the patient diagnosed with PHP-Ic, G(s)alpha protein was shortened by just four amino acids, a finding consistent with the conservation of G(s) activity in erythrocytes and the loss of receptor contact. No GNAS1 lesions were found in individuals with isolated AHO that were not relatives to PHP-Ia patients (n = 5). Intrafamilial segregation analyses of the mutated GNAS1 allele in nine PHP-Ia patients established that the mutation had either occurred de novo on the maternal allele (n = 4) or had been transmitted by a mother with a mild phenotype (n = 5). This finding is consistent with an imprinting of GNAS1 playing a role in the clinical phenotype of loss of function mutations and with a functional maternal GNAS1 allele having a predominant role in preventing the hormonal resistance of PHP-Ia.

    The Journal of clinical endocrinology and metabolism 2002;87;1;189-97

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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